1. Field
This application relates generally to biocompatible water-soluble polymers with pendant functional groups and methods for making them, and particularly to co-polymer polyglutamate amino acid conjugates useful for a variety of drug delivery applications, e.g., anti-cancer.
2. Description
A variety of systems have been used for the delivery of drugs. For example, such systems include capsules, liposomes, microparticles, nanoparticles, and polymers. Several polyester-based biodegradable systems have been characterized and studied. Polylactic acid (PLA), polyglycolic acid (PGA) and their copolymers polylactic-co-glycolic acid (PLGA) are some of the most well-characterized biomaterials with regard to design and performance for drug-delivery applications. See Uhrich, K. E.; et al., Chem. Rev. (1999) 99:3181-3198 and Panyam J. et al., Adv Drug Deliv Rev. (2003) 55:329-47. Biodegradable systems based on polyorthoesters have also been investigated. See Heller, J. et al., Adv. Drug Del. Rev. (2002) 54:1015-1039. Additionally, polyanhydride systems have been investigated. Such polyanhydrides are typically biocompatible and may degrade in vivo into relatively non-toxic compounds that are eliminated from the body as metabolites. See Kumar, N. et al., Adv. Drug Del. Rev. (2002) 54:889-91.
Amino acid-based polymers have been considered as a potential source of new biomaterials. Poly-amino acids having good biocompatibility have been investigated to deliver low molecular-weight compounds. A relatively small number of polyglutamic acids and copolymers have been identified as candidate materials for drug delivery. See Bourke, S. L. et al., Adv. Drug Del. Rev. (2003) 55:447-466.
Administered hydrophobic anti-cancer drugs, therapeutic proteins and polypeptides often suffer from poor bio-availability. Such poor bio-availability may be due to incompatibility of bi-phasic solutions of hydrophobic drugs and aqueous solutions and/or rapid removal of these molecules from blood circulation by enzymatic degradation. One technique for increasing the efficacy of administered proteins and other small molecule agents entails conjugating the administered agent with a polymer, such as a polyethylene glycol (“PEG”) molecule, that can provide protection from enzymatic degradation in vivo. Such “PEGylation” often improves the circulation time, and, hence, bio-availability of an administered agent.
PEG has shortcomings in certain respects, however. For example, because PEG is a linear polymer, the steric protection afforded by PEG is limited, as compared to branched polymers. Another shortcoming of PEG is that it is generally amenable to derivatization at its two terminals. This limits the number of other functional molecules (e.g. those helpful for protein or drug delivery to specific tissues) that can be conjugated to PEG.
Polyglutamic acid (PGA) is another polymer of choice for solubilizing hydrophobic anti-cancer drugs. Some anti-cancer drugs conjugated to PGA have been reported. See Chun Li. Adv. Drug Del. Rev, (2002) 54:695-713. However, none of these PGA polymers are currently FDA-approved.
Paclitaxel, extracted from the bark of the Pacific Yew tree (Wani et al., J Am Chem Soc. (1971) 93:2325-7), is a FDA-approved drug for the treatment of ovarian cancer and breast cancer. However, like other anti-cancer drugs, paclitaxel suffers from poor bio-availability due to its hydrophobicity and insolubility in aqueous solution. One way to solubilize paclitaxel is to formulate it in a mixture of Cremophor-EL and dehydrated ethanol (1:1, v/v) (Sparreboom et al., Cancer Research (1999) 59:1454-1457). This formulation is currently commercialized as Taxol® (Bristol-Myers Squibb). Another method of solubilizing paclitaxel is by emulsification using high-shear homogenization (Constantinides et al., Pharmaceutical Research (2000) 17:175-182). Polymer-paclitaxel conjugates have been advanced in several clinical trials (Ruth Duncan, Nature Reviews Drug Discovery (2003) 2:347-360). Paclitaxel has been formulated into nano-particles with human albumin protein, which has been used in clinical studies (Damascelli et al., Cancer. (2001) 92:2592-602, and Ibrahim et al., Clin Cancer Res. (2002) 8:1038-44). This formulation is currently commercialized as Abraxane® (American Pharmaceutical Partners, Inc.).